In just three years, Bristol-Myers Squibb (BMS) received more than 10 approvals for Opdivo (nivolumab), authored 12 publications in the New England Journal of Medicine, and was granted seven Breakthrough Therapy designations by the U.S. Food and Drug Administration.
“We are at the golden age of oncology,” said Fouad Namouni, MD, head of Oncology Development at BMS, introducing a presentation and panel discussion session at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid.
But with all the positive results of Yervoy (ipilimumab) and Opdivo, the two major BMS immunotherapies, what are the new trends in the field of immuno-oncology (IO)?
Researching IO earlier in the disease
Vicki Goodman, MD, head of New Asset Development at BMS, reminds us that immunotherapy can be used early in two settings: as adjuvant therapy to prevent recurrence after surgery, and as neo-adjuvant therapy to shrink the tumor before surgery or radiotherapy.
Yervoy, for example, was shown to reduce the risk of cancer returning in melanoma. But in a Phase 3 trial where it was compared with Opdivo in advanced melanoma patients at high risk of recurrence after surgery — the Checkmate-238 trial (NCT02388906) — Opdivo-treated patients had a 35 percent smaller chance of seeing their cancer return.
While both drugs are checkpoint inhibitors, they target different checkpoint molecules. Opdivo blocks PD-L1 while Yervoy prevents the actions of CTLA-4.
How biomarkers may predict patient response
Checkpoint inhibitors mainly work by targeting effector T-cells — immune cells with the ability to target and kill cancer cells — boosting their activity. But David Feltquate, an MD and PhD, head of Early Clinical Development at BMS, pointed out that there is a lot to consider when dealing with immunotherapies.
The actions of T-cells might be impaired by a variety of factors, including molecules produced by tumor and tumor-supporting (stroma) cells. And other immune cells, like dendritic cells or macrophages, can be hijacked by the tumor and dampen T-cell reaction.
Therefore, there is a major need for biomarkers that predict response to immunotherapies.
Researchers have been using PD-L1 to predict response in solid tumors since 2015. For drugs targeting PD-L1, like Opdivo, patients are more likely to respond if their tumors have high levels of this molecule. And the same is true for other drugs specific for the PD-L1 receptor, PD-1.
More recently, researchers began using the genetic biomarker, microsatellite instability-high, or MSI-H, as a predictor of immunotherapy response.
The genetic abnormalities in tumors with MSI-H impair the ability of cells to repair DNA, leading to an accumulation of mutations in tumor cells. The mutations can generate structurally different proteins that the immune system identifies as malignant. As a result, the more mutations a tumor has, the more visible it becomes to the immune system.
Feltquate believes that the next biomarkers in the future will be tumor mutational burden (TMB), for the same reasons as MSI-H, as well as the expression of LAG-3 on the immune cells surrounding the tumor. Similar to PD-1 and CTLA-4, LAG-3 is another immune checkpoint that prevents immune cells from attacking the tumor.
Building rational combinations
Because targeting one single molecule might not be enough for a number of cancers, researchers have been working on combination therapies that are more effective at eliminating cancer for good and improving patients’ survival.
Data presented during the ESMO 2017 Conference has shown that BMS’ immunotherapies can be combined to lengthen the survival of kidney cancer patients.
Highlighting results from the CheckMate-214 Phase 3 trial (NCT02231749), Goodman showed that Opdivo plus Yervoy nearly doubled the response rate in previously untreated renal cell carcinoma patients, compared to the current standard of care, Sutent (sunitinib). And the combo increased survival by 37 percent.
The study was stopped early, due to a compelling demonstration of efficacy.
Emerging topics: addressing resistance
Resistance to checkpoint inhibitors, primary or secondary, concerns many patients. Primary resistance is when new patients who have never taken the drug do not respond. Secondary resistance is when a patient first responded to the drug but then relapsed.
During the presentation, Feltquate revealed the example of a patient with advanced melanoma who had responded to Opdivo for over a year, after which the cancer returned. The patient was given a combination of Opdivo plus an anti-LAG-3 therapy, and at four months the disease had nearly completely disappeared.
The findings suggest that for patients whose immune cells express LAG-3, this could be a good approach to overcome resistance to Opdivo.
Panel discussion and Q&A
What is the role of translational medicine?
Dr. John B. Haanen, head of the Division of Medical Oncology and staff scientist in the Division of Immunology at the Netherlands Cancer Institute Amsterdam, points out that targeting the immune system is much more complex than targeting just one protein.
He says that doctors need to take biopsies and look at the tissue to see what is going on. It is all the more difficult as the disease is different for each patient, and even in tumors from the same patient.
“We need to get the full picture of the tumor, with PD-L1, LAG-3, IDO [another immune checkpoint], to move towards personalization of the treatment,” added Dr. Paolo A. Ascierto, director at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, at the National Tumor Institute “Fondazione G. Pascale” in Naples, Italy.
There is also the need to identify cold tumors, those with few infiltrating T-cells and less likely to respond to checkpoint inhibitors, and how these tumors can be transformed into hot (inflamed) tumors.
Also, researchers need to understand what drives primary resistance to immunotherapy, said Haanen. “Is there no mutation, no T-cells?” These are important questions that we need to address.
How do you establish combination therapies?
“The combinations are not selected by chance; there is a rationale,” Haanen said. With biopsies, researchers can identify the mechanism of resistance, and find the right targets. But we need well-designed clinical trials to test these combinations.
Do these treatments actually make patients live longer?
Early treatment can change the course of the disease. Some patients may not require surgery after early immunotherapy. Still, researchers should keep in mind the toxicity of these treatments, and learn how to manage it.
What are the good endpoints for clinical trials? (response rate, PFS or overall survival)
Overall survival is the most important endpoint. But some other endpoints, such as median progression-free survival, can be good surrogates.
Do we have good biomarkers for response to treatment?
“We don’t have a good biomarker at the moment,” Haanen said. The accuracy of PD-L1 and TMB is still far from desired, he explained. T-cell infiltration may be the best biomarker right now. Also, MSI-H is a very good predictor of response in colorectal cancers.
What do you think of safety issues with the myeloma trial?
When immune tolerance is perturbed, auto-immunity can occur. This effect is major with CTLA-4 inhibitors, like Keytruda (pembrolizumab), and may be lesser with other targets.
For example, it appears that the combination of Opdivo with anti-LAG-3 has a comparable safety profile as the monotherapy. But it is true that we need to better manage the toxicity of these treatments.
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